Placenta
Volume 28, Supplement , Pages S48-S50, April 2007

Oxidative Stress and Pregnancy Outcome: A Workshop Report

  • N. Sugino

      Affiliations

    • Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan
    • Corresponding Author InformationCorresponding author. Tel.: +81 836 22 2286; fax: +81 836 22 2287.
    • ,
  • S. Takiguchi

      Affiliations

    • Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan
    • ,
  • T. Umekawa

      Affiliations

    • Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan
    • ,
  • A. Heazell

      Affiliations

    • Maternal and Fetal Health Centre, St Mary's Hospital, Manchester, UK
    • ,
  • I. Caniggia

      Affiliations

    • Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada

Accepted 24 January 2007. published online 13 March 2007.

Article Outline

Keywords: Oxidative stress, Miscarriage, IUGR, Preeclampsia

 

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1. Introduction 

Cells living under aerobic conditions always face oxygen paradox. While physiological levels of oxygen are necessary for cells to maintain their lives, toxic reactive oxygen species (ROS) such as superoxide radical (O2−), hydroxyl radical (OH−) and hydrogen peroxide (H2O2) are generated from oxygen following conditions of oxidative stress. Elevated ROS have been reported to have detrimental consequences on the cells as they can cause DNA and protein damage and lipid peroxidation which primarily affects membrane structure and function. Interestingly, data have recently shown that physiological levels of ROS can regulate cell function by both controlling production and activation of substances that have biological activities and by activating key downstream cell signaling pathways. On the other hand, to control for the potential adverse consequences of ROS production, cells under aerobic conditions have unique defense systems against ROS. Indeed, known specific metallo-enzymes are able to scavenge superoxide radicals: copper-zinc superoxide dismutase (Cu,Zn-SOD), located in the cytosol, and manganese SOD (Mn-SOD), located in the mitochondria. A tightly regulated balance between ROS generation and scavenging enzymes production is therefore required in physiological aerobic conditions. Disruption of this balance due to oxidative stress conditions occurs as a consequence of excessive production of ROS or impaired antioxidant defense systems. It has been reported that oxidative stress and a disrupted antioxidant system are involved in a variety of pregnancy complications such as preterm labor, fetal growth restriction, preeclampsia, and miscarriage [1], [2]. The objectives of this workshop were to provide new information regarding the involvement of oxidative stress in the pathophysiology of pregnancy complications.

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2. Oxidative stress in the decidua of spontaneous miscarriage 

Spontaneous miscarriage is the most common complication of early pregnancy. S. Takiguchi addressed the role of oxidative stress in decidual samples obtained from termination of pregnancies following spontaneous miscarriages. The potential role of superoxide radicals on prostaglandin F2α (PGF2α) synthesis in human endometrial stromal cells was reviewed [3], [4], [5], [6], [7], [8], [9], [10]. Withdrawal of progesterone causes generation of superoxide radicals in the cytosol in endometrial stromal cells through the decrease in Cu,Zn-SOD expression, and in turn superoxide radicals stimulate cyclooxygenase-2 (COX-2) expression and subsequent PGF2α synthesis by activating a transcription factor, NF-κB. Because PGF2α is a powerful inducer for uterine contraction, increased PGF2α production induced by oxidative stress in the decidua may contribute to expulsion of uterine content during spontaneous miscarriages. Cu,Zn-SOD values, concentrations of lipid peroxide (LPO) and PGF2α, and COX-2 mRNA levels were next analyzed in the decidua obtained from normal pregnancy and failed pregnancy. Failed pregnancy was divided into two groups: spontaneous miscarriage with or without vaginal bleeding and abdominal pain. While in spontaneous miscarriage with vaginal bleeding Cu,Zn-SOD activities and Cu,Zn-SOD mRNA levels in the decidua were significantly lower, concentrations of LPO and PGF2α, and COX-2 mRNA levels were significantly higher than those found in normal pregnancy and spontaneous miscarriage without vaginal bleeding (missed miscarriage). No significant difference in all of these parameters between normal pregnancy and missed miscarriage were found. It was concluded that during early pregnancy oxidative stress experienced by the decidua is involved in the pathogenesis of spontaneous miscarriage, and this is likely mediated through the increase in PGF2α synthesis. In other words, the antioxidant system in the decidua may contribute to uterine quiescence by preventing oxidative stress that causes PGF2α synthesis. Furthermore, it was found that oxidative stress and the subsequent increased PGF2α synthesis had not yet occurred in the decidua of missed miscarriage, suggesting an interesting possibility regarding the pathophysiology of missed miscarriage. Further studies are needed to establish the trigger responsible for the decrease in Cu,Zn-SOD expression in the decidua of spontaneous miscarriage and to establish the mechanisms underlying the different mode of miscarriages.

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3. Roles of the placental antioxidant system in fetal growth 

It has been reported that placental oxidative stress and disrupted antioxidant system are involved in fetal growth restriction [1], [11], [12]. T. Umekawa addressed the role of the placental antioxidant system in fetal growth. It has been reported that thioredoxin-1 works as an antioxidant and is expressed in the placenta [13]. Systemic human thioredoxin-1 (hTRX-1) overexpressing transgenic mice were used to study the role of this novel placental antioxidant system. Systemic hTRX-1 transgenic female mice and wild type female mice were mated with wild type male mice. On day 15 of pregnancy, in addition to the weight of fetuses and placentas, protein and mRNA expression of hTRX-1 and mouse TRX levels were measured in the placenta. To evaluate oxidative stress in the placenta, production of 8-hydroxy-2′-deoxyguanosine (8-OH-dG) was assessed by immunohistochemistry. The placenta weight of hTRX-1 transgenic mice was significantly lower than that of wild type mice, whereas there was no significant difference in fetal weights between both groups. Mouse TRX-1 expression was observed in the placenta of both groups, and hTRX-1 expression was detected only in the placenta of hTRX-1 transgenic mice. 8-OH-dG production was apparent in the placenta of wild type mice while placentas of hTRX-1 transgenic mice showed very weak 8-OH-dG expression. Furthermore, insulin-like growth factor-1 (IGF-1) mRNA expression was lower while IGF-binding protein-2 (IGFBP-2) mRNA expression was higher in the placenta of hTRX-1 transgenic mice. It was concluded that although placentas are smaller in hTRX-1 transgenic mice, functions such as production of some growth factors are working to maintain fetal growth because of the increased antioxidant system in the placenta. However, further studies are needed regarding the roles of the placental antioxidant system, including the possible roles of IGF-1 and IGFBP-2, in fetal and placental growth.

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4. Apoptosis caused by ROS and hypoxia in the placenta 

Increased apoptotic cell death has been described in the syncytiotrophoblast cells of placentas from pregnancies complicated by preeclampsia [14], [15], [16], [17]. It is also established that the increase in apoptosis occurs as a result of exposure of the placenta to hypoxia/oxidative stress [1], [2], [16], [18], [19]. Furthermore, hypoxic conditions of the placenta are well known in preeclampsia [20], [21]. A. Heazell reported the effects of hypoxia and oxidative stress on apoptosis of trophoblasts. For this purpose, placental villous explants were incubated with hydrogen peroxide (as oxidative stress), or under conditions of hypoxia (1% O2) and normoxia (6% O2). Apoptosis was assessed by a TUNEL analysis. Apoptotic cell death was increased by exposure to hypoxia compared with normoxia. In addition, apoptosis was increased by the treatment with hydrogen peroxide in a dose-dependent manner. Apoptotic cells were predominantly detected in syncytiotrophoblast layers. These findings indicate that in the human placenta apoptosis is induced not only by oxidative stress but also by hypoxia. A close relationship was shown between oxidative stress and apoptosis of syncytiotrophoblasts features that is often observed in preeclamptic placentas. The difference was discussed in the potential mechanisms involved in the induction of apoptosis between oxidative stress and hypoxia. Data showed that ROS increased pro-apoptotic p53 but did not alter the expression of anti-apoptotic Mdm2 in the syncytiotrophoblast cells, whereas, in contrast, exposure of explants to hypoxia did not affect p53 expression but increased Mdm2 expression in the syncytiotrophoblast cells. Further studies are needed to better understand the precise effect/role of ROS and hypoxia on trophoblast cell fate in physiological and pathological conditions.

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5. Conclusions and future importance 

This workshop has highlighted the importance of a proper balance between oxidative stress and antioxidant systems during pregnancy. Importantly, the speakers have provided novel insight into the detrimental consequences following alteration of this balance. In fact, each speaker clearly provided novel information regarding the involvement of hypoxia/oxidative stress in the pathophysiology of a variety of pregnancy complications including spontaneous miscarriage, fetal growth, and in trophoblast-related disorders such as preeclampsia. Oxidative stress following hypoxic conditions is an important factor that is related to pregnancy complications such as miscarriage, IUGR, and preeclampsia. From the overall discussion/debate it was concluded that changes in oxygen levels experienced in uterus by both the fetus and the placenta may have opposing effects depending upon the physiological (good hypoxia) and pathological scenario (bad hypoxia). As such it is important to understand the differences between physiological “hypoxia” and its role on the production of the proper amount of ROS and anti-oxidant enzymes and conditions of oxidative stress, which are often accompanied by elevated ROS generation and decreased defense mechanisms. Greater collaboration and communication between scientists working on oxidative stress, hypoxia and pregnancy outcome is essential to address some of the important questions about the role of oxidative stress and hypoxia in pregnancy complications.

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References 

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PII: S0143-4004(07)00017-3

doi:10.1016/j.placenta.2007.01.013

Placenta
Volume 28, Supplement , Pages S48-S50, April 2007

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